ABSTRACT Retinitis Pigmentosa (RP) is a group of inherited retinal diseases resulting from one or more of a large number of genetic mutations. It is a major cause of blindness and severe vision loss in people aged 20-60 years. The first symptom is loss of night vision as a result of mutation-caused death of rod photoreceptors. Subsequently loss of cone photoreceptors begins, and patients experience gradual loss of visual field until become legally blind. Currently, there is no treatment for preventing vision loss in RP. Mechanistic studies have shown that death of rods results in elevated tissue-level of oxygen in the outer retina. Exposure to the excessive oxidative stress leads to progressive damage and death of the cone cells. Therefore, reducing oxidative stress in cones can be a viable therapeutic target for preserving cones in RP, and potent antioxidants are thought to promote cone survival and function in patients with RP. Cones provide vision under photopic lighting which is critical for daily activities, thus preventing cone degeneration can prevent visual disability and blindness in patients with RP. N-Acetylcysteine (NAC) is a well-known antioxidant and available as a generic medication for treatment of acetaminophen overdose and as a dietary supplement. Animal studies reported that orally administered NAC reduced cone cell death and preserved cone function by reducing oxidative damage in two mice models of RP. A recent phase-1 open label dose-ranging study enrolled 30 RP patients and followed them for 6-months at the Wilmer Eye Institute (clinicaltrial.gov NCT03063021). The study demonstrated that oral NAC was safe and that dosages up to 1800mg/bid were well tolerated in patients with RP. A multicenter, randomized, placebo-controlled phase-2 clinical trial therefore is warranted to determine the safety and efficacy of long-term NAC treatment in slowing progression of RP. Support is being requested for the planning of the multicenter phase-2 trial, to 1). Develop a manual of procedures, data collection forms, and other materials required to conduct the phase-2 trial; 2).Develop procedures for the trial Coordinating Center and the resource centers, including an Image Reading Center, the drug acquisition and distribution center, and the central chemistry laboratory; 3). Create an organizational structure to facilitate, guide, conduct, and monitor the multicenter study; and 4). Further refine the design of the phase-2 trial through incorporating information generated from the ongoing extension study of the phase-1 dose-ranging study participants and a study of the natural history of RP. Procedures and materials developed from this planning grant will ensure successful conduct of the phase -2 trial to achieve the specific aims of 1). Evaluating the rates of anatomic and functional changes over 24-months in RP patients receiving 1200mg bid or 1800mg bid oral NAC compared to patients receiving placebo; and 2) determining an efficacious dosage by comparing rates of anatomic and functional changes between the 1200mg bid and 1800mg bid dosage groups.